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Ophthalmology Management

Article

The rise of epithelial thickness mapping

ETM is an essential tool for the diagnosis and management of keratoconus.

By: Aleksandar Stojanovic, MD, PhD, Yue Feng, MD
Ophthalmology Management June 1, 2021 Vol 25, Issue June 2021 Page(s): 52, 54, 56

As its first refractive medium, the corneal epithelium has an important role in the refractive system of the eye. Cornea with the epithelium on has a lower refractive power than deepithelialized cornea, since the epithelium increases the corneal radius of curvature by its thickness.1 Refraction may also be affected by slightly different refractive index between the epithelium and the stroma. Epithelium influences corneal refraction also due to its non-uniform thickness profile caused by the effect of eyelid blinking mechanics2 and due to inherent smoothening behavior of the epithelial cells that even out the underlying stromal surface irregularities.3 The latter normally decreases the refractive power, negative asphericity, astigmatism and higher-order aberrations on the stroma.

This phenomenon, known as epithelial remodeling,4-8 smoothens the stromal surface up to its compensatory capacity, to achieve more regular surface and optics on the anterior cornea. In that respect, epithelium proportionally thickens over the stromal depressions and grows thinner over the protrusions. According to Reinstein’s research, the compensatory capacity of the epithelial remodeling is dictated by the rate of change of the stromal curvature.9 In extreme cases, a sharp spike on the stroma would be totally compensated by the epithelial remodeling, while very gradual stromal irregularities would not be compensated at all and will appear unchanged on the anterior corneal surface (Figure 1).

Figure 1. Epithelial remodeling as a function of rate of change of stromal curvature. A. Sharp spikes and divots on top of the stroma are totally compensated by the epithelial remodeling. B. Gradual stromal irregularities are not compensated at all and appear unchanged on the anterior corneal surface.
Figure 1. Epithelial remodeling as a function of rate of change of stromal curvature. A. Sharp spikes and divots on top of the stroma are totally compensated by the epithelial remodeling. B. Gradual stromal irregularities are not compensated at all and appear unchanged on the anterior corneal surface.

Keratoconic corneas feature very pronounced surface irregularities and are therefore the subject for intense epithelial remodeling resulting in a donut-shaped epithelial pattern characterized by compensatory thinning over the cone with a surrounding annulus of thicker epithelium.6

EARLY DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

In early keratoconus (KC), the epithelial remodeling may mask the protrusion of the cone and hide it from the anterior surface topography (Figure 2). Epithelial thickness mapping (ETM) may in that respect serve as an early KC indicator,10 with its specific pattern that absorbs the underlying stromal changes. Hence, the ETM may be thought of as an inverse stromal surface topography. Findings by Randleman JB et al, which report normal preoperative topography in 25 of 93 patients (27%) who developed corneal ectasia after refractive surgery,11 show that the corneal topography may not be sufficient to detect all cases with early KC and keratectasia and that the additional diagnostic help by the ETM may be crucial in this respect.

Figure 2. Epithelial thickness mapping in early detection of keratoconus (KC). A. Anterior axial curvature topography by Nidek OPD-Scan II showing inconclusive amount of inferior steepening. B. Corneal pachymetry (left) and epithelial thickness map (right) measured by Avanti SD-OCT (Optovue), the latter showing a “donut-shaped” epithelial thickness pattern over a parasentral cone and confirming KC diagnosis.
Figure 2. Epithelial thickness mapping in early detection of keratoconus (KC). A. Anterior axial curvature topography by Nidek OPD-Scan II showing inconclusive amount of inferior steepening. B. Corneal pachymetry (left) and epithelial thickness map (right) measured by Avanti SD-OCT (Optovue), the latter showing a “donut-shaped” epithelial thickness pattern over a parasentral cone and confirming KC diagnosis.

On the other hand, cases with normal corneal stroma in conditions involving epithelial changes may appear as early KC on the anterior corneal topography. Due to irregularities such as inferior steepening, they may mimic KC on anterior corneal topography and lead to inaccurate diagnosis. The three cases presented on Figure 3 show the power of ETM as a differential diagnostic tool. The anterior corneal topography showing inferior steepening pattern in all three cases may be explained by ETM. Epithelial thinning above the cone shows an early KC in case 1 (Figure 3A), while epithelial thickening in cases 2 (Figures 3B) and 3 (Figure 3C) is due to anterior basement membrane dystrophy and lens-induced warpage, respectively. These three cases were all considered for LASIK. Without the differential diagnostic help from the ETM, two of them would have been wrongly rejected as non-candidates for the surgery.

Figure 3. Epithelial thickness mapping for differential diagnosis for candidacy in laser vision correction. Upper row shows anterior axial Placido topographies in three candidates for laser vision correction. Lower row shows epithelial thickness maps measured by Optovue RT-100 (6-mm diameter) showing: a. keratoconus pattern; b. anterior basement membrane dystrophy; c. epithelial warpage due to contact lens use.
Figure 3. Epithelial thickness mapping for differential diagnosis for candidacy in laser vision correction. Upper row shows anterior axial Placido topographies in three candidates for laser vision correction. Lower row shows epithelial thickness maps measured by Optovue RT-100 (6-mm diameter) showing: a. keratoconus pattern; b. anterior basement membrane dystrophy; c. epithelial warpage due to contact lens use.

ETM IN EVALUATION OF KC PROGRESSION BEFORE AND AFTER CXL

Stromal protrusion in KC gets initially compensated by epithelial remodeling so that anterior topography findings in progressive KC may still appear stable. In addition, if changes detected by posterior corneal topography become inconclusive due to decreased corneal transparency in the cone area, ETM may remain the only tool to provide reliable information about KC progression (Figure 4) and indicate the need for treatment.10

Figure 4. Keratoconus progression detected by epithelial thickness mapping (ETM). Upper row: Anterior axial curvature topographies (baseline, left; 3-months follow-up, middle) and the differential map (right), measured by Anterion SS-OCT (Heidelberg), showing no progression. Lower row shows ETMs of the same eye and on same dates (baseline, left; 3-months follow-up, right) measured by Avanti SD-OCT (Optovue) showing progression.
Figure 4. Keratoconus progression detected by epithelial thickness mapping (ETM). Upper row: Anterior axial curvature topographies (baseline, left; 3-months follow-up, middle) and the differential map (right), measured by Anterion SS-OCT (Heidelberg), showing no progression. Lower row shows ETMs of the same eye and on same dates (baseline, left; 3-months follow-up, right) measured by Avanti SD-OCT (Optovue) showing progression.

Corneal cross-linking (CXL) is currently the only treatment addressing the core of the problem in KC. It aims to stiffen and stabilize the biomechanically compromised cornea by increasing the tensile strength and rigidity of the cornea. ETM changes after CXL for KC may show either signs of stabilization and diminishing protrusion by demonstrating compensatory relative epithelial thickening over the cone or, if the effect of CXL is insufficient, the ETM will reveal continuous thinning. In both these cases, the anterior corneal topography may remain stable, making the ETM the most sensitive diagnostic method for monitoring the effect of the CXL treatment.12

Figure 5. Epithelial thickness maping (ETM) for follow-up after corneal cross-linking (CXL) for keratoconus. Avanti SD-OCT (Optovue) ETM before CXL (left) and 4 months postoperatively (right) show regularization and the desired effect after the treatment.
Figure 5. Epithelial thickness maping (ETM) for follow-up after corneal cross-linking (CXL) for keratoconus. Avanti SD-OCT (Optovue) ETM before CXL (left) and 4 months postoperatively (right) show regularization and the desired effect after the treatment.

ETM TECHNOLOGY

Different technologies for mapping of the corneal epithelial thickness have appeared, starting with the very high-frequency (VHF) digital ultrasound scanning (Artemis, ArcScan) as early as 2001. Although it still provides the most precise ETMs, Artemis never became a prevalent instrument for routine clinical use, most likely due to the examination requiring direct contact with the cornea by use of saline immersion and due to a relatively long acquisition time. Another not currently prevalent ETM technology is featured by Precisio 2 (Ivis Technologies). It is based on ultrathin (30 μm) blue (450 nm wavelength) laser-light rotating slit, which allows precise corneal sublayer imaging and wide diameter epithelial mapping.

OCT

Although the OCT-based ETM appeared years after the VHF digital ultrasound scanning, without surpassing the latter in its precision, it became by far the most used technology in everyday practice of ophthalmologists. It is based on low-coherence interferometry using near-infrared light to provide high-resolution information on layered corneal tissue morphology. The first OCT-based instrument to provide ETM was Optovue RT-100, using spectral-domain (SD)-OCT technology, which is also used in the more recent Optovue Avanti as well as in several other SD-OCT instruments used for imaging both posterior and anterior eye segments. Avanti SD-OCT, probably the most prevalent instrument at this time, uses a light source emitting at 840-nm and provides axial resolution of 5 μm and transversal resolution of 15 μm. The instrument, otherwise used for posterior segment imaging, employs an adaptor lens for corneal and anterior segment imaging.

MS-39 (CSO), an OCT instrument for only anterior segment imaging that features ETM, is a hybrid technology that combines SD-OCT with Placido disc corneal topography. The MS-39 uses a SLED light source emitting at 845 nm and provides axial resolution of 3.6 μm (in tissue) and transversal resolution of 35 μm (in the air). High ETM repeatability of MS-39 was reported in both KC and healthy eyes.13,14

Anterion (Heidelberg Engineering) and Casia 2 (Tomey Corporation), both anterior segment-only OCTs using swept-source (SS)-OCT technology, have yet to release their ETM capabilities that are currently under clinical trials. This function is present only in its investigational software version and has not been released commercially.

The Anterion SS-OCT uses a 1300-nm light source, providing axial resolution of <10 μm and transversal resolution of 30 μm. The long wavelength of the Anterion SS-OCT allows for evaluation of the whole anterior segment, and the lateral scanning SS-OCT allows for cross-sectional imaging. Casia 2 SS-OCT uses a 1310-nm light source, providing axial resolution of 10 μm and transversal resolution of 30 μm. Its SS-OCT technology achieves higher penetration but lower resolution than SD-OCT devices. It uses a CMOS camera instead of spectrometer.

TABLE 1. SPECIFICATIONS OF THE OCT DEVICES FOR ETM
DEVICE ANTERION CASIA 2 AVANTI MS-39
Light source wavelenngth (nm) 1300 1310 840 845
A-scan speed 50,000 50,000 70,000 102,400
Axial resolution (μm) <10 10 5 3.6
Transverse resolution (μm) 30 30 15 35
A-scan depth (mm) 14+/-0.5 13 3 7.5
Maximum scan width (mm) 16.5 16 12 16
B scan 65 × 1 16 × 1 8 × 5 10 × 5
Number of A-scans per B-scan 768 800 1024 1024

CONCLUSION

Epithelial remodeling in KC “absorbs” the stromal surface irregularities and “hides” them from appearing on the anterior surface topography. For that reason, the ETM may be the best method of early detection of the disease as well as in differential diagnosis in suspect corneal topography findings. ETM is also an essential tool in follow-up of the KC progression and in evaluation of the effectiveness in KC management. OM

References

  1. Simon G, Ren Q, Kervick GN, Parel JM. Optics of the corneal epithelium. Refract Corneal Surg. 1993;9:42-50.
  2. Reinstein DZ, Silverman RH, Coleman DJ. High-frequency ultrasound measurement of the thickness of the corneal epithelium. Refract Corneal Surg. 1993;9:385-387.
  3. Reinstein DZ, Archer TJ, Gobbe M. Corneal epithelial thickness profile in the diagnosis of keratoconus. J Refract Surg. 2009;25:604-610.
  4. Reinstein DZ, Srivannaboon S, Gobbe M, et al. Epithelial thickness profile changes induced by myopic LASIK as measured by Artemis very high-frequency digital ultrasound. J Refract Surg. 2009;25:444-450.
  5. Reinstein DZ, Archer TJ, Gobbe M, et al. Epithelial thickness after hyperopic LASIK: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2010;26:555-564.
  6. Reinstein DZ, Archer TJ, Gobbe M. Corneal epithelial thickness profile in the diagnosis of keratoconus. J Refract Surg. 2009;25:604-610.
  7. Rocha KM, Perez-Straziota CE, Stulting RD, Randleman JB. SD-OCT analysis of regional epithelial thickness profiles in keratoconus, postoperative corneal ectasia, and normal eyes. J Refract Surg. 2013;29:173-179.
  8. Zhou W, Stojanovic A. Comparison of corneal epithelial and stromal thickness distributions between eyes with keratoconus and healthy eyes with corneal astigmatism >/= 2.0 D. PloS One. 2014;9:e85994.
  9. Reinstein DZ, Archer TJ, Gobbe M. Rate of change of curvature of the corneal stromal surface drives epithelial compensatory changes and remodeling. J Refract Surg. 2014;30:799-802.
  10. Reinstein DZ, Gobbe M, Archer TJ, et al. Epithelial, stromal, and total corneal thickness in keratoconus: three-dimensional display with artemis very-high frequency digital ultrasound. J Refract Surg. 2010;26:259-271.
  11. Randleman JB, Dupps Jr WJ, Santhiago MR, et al. Screening for Keratoconus and Related Ectatic Corneal Disorders. Cornea. 2015;34:e20-e22.
  12. Reinstein DZ, Gobbe M, Archer TJ, Couch D. Epithelial thickness profile as a method to evaluate the effectiveness of collagen cross-linking treatment after corneal ectasia. J Refract Surg. 2011;27:356-363.
  13. Savini G, Schiano-Lomoriello D, Hoffer KJ. Repeatability of automatic measurements by a new anterior segment optical coherence tomographer combined with Placido topography and agreement with 2 Scheimpflug cameras. J Cataract Refract Surg. 2018;44:471-478.
  14. Schiano-Lomoriello D, Bono V, Abicca I, Savini G. Repeatability of anterior segment measurements by optical coherence tomography combined with Placido disk corneal topography in eyes with keratoconus. Sci Rep. 2020;10:1124.

About the Author

Aleksandar Stojanovic, MD, PhD, is an associate clinical professor at University of Tromsø, Norway, and a senior consultant in charge of therapeutic refractive surgery and keratoconus at the eye department at University Hospital of Northern Norway in Tromsø.

Aleksandar Stojanovic, MD, PhD, is an associate clinical professor at University of Tromsø, Norway, and a senior consultant in charge of therapeutic refractive surgery and keratoconus at the eye department at University Hospital of Northern Norway in Tromsø.

Yue Feng, MD, is a PhD student at the University of Tromsø in Norway. The subject of her study is corneal imaging.

Yue Feng, MD, is a PhD student at the University of Tromsø in Norway. The subject of her study is corneal imaging.

The authors report no relevant financial disclosures

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